title: Discovery of novel tetrahydro-pyrazolo [4,3-c] pyridines for the treatment of neuropathic pain: synthesis and neuropharmacology.
abstract: We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB₁). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4-bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED₅₀ = 23.8 mg/kg) and partial sciatic nerve injury (ED₅₀ = 29.0 mg/kg) models with CB₁ receptor activity (IC₅₀ = 49.6 nM) and inhibitory effect on TNF-α (86.4% inhibition at 100 mg/kg). These results suggest the importance of the development of this lead as multi-targeted treatment strategy for neuropathic pain.
authors.affiliation: Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, RR District, 500078 Andhra Pradesh, India. pyogee@hyderabad.bits-pilani.ac.in
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Monika
authors.initials: M
authors.lastname: Sharma
authors.forename: Ganesh
authors.initials: G
authors.lastname: Samala
authors.forename: Matharasala
authors.initials: M
authors.lastname: Gangadhar
authors.forename: Srirama
authors.initials: S
authors.lastname: Karthick
authors.forename: Saketh
authors.initials: S
authors.lastname: Mallipeddi
authors.forename: Arvind
authors.initials: A
authors.lastname: Semwal
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009480:Neuropharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D043882:Receptors, Cannabinoid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D014409:Tumor Necrosis Factor-alpha; C031280:pyrazole
keywords: Antiallodynic; Antihyperalgesic; Antioxidant; Cannabinoid receptor; Nitric oxide; Tetrahydropyrazolo-pyridine